Imidazol derivatives

ABSTRACT

This invention relates to novel imidazole derivatives of formula a ##STR1## and pharmaceutically acceptable salts of these compounds, wherein R 1 , R 2 , R 3 , R 5 , R 7  and R 8  are as disclosed herein. These compounds are protein kinase inhibitors useful in the treatment of atherosclerosis, psoriasis, alopecia, and tumors.

This application is a 371 of PCT/EP95/04741 filed Dec. 12, 1995.

The invention is concerned with novel imidazole derivatives of thegeneral formula ##STR2## wherein R¹ signifies lower-alkyl or halogen, R²signifies hydrogen, hydroxy, nitro, lower-alkoxycarbonyl,di(lower-alkyl) amino-lower-alkyl, morpholino-lower-alkyl or4-methylpiperazinyl-lower-alkyl, R³ signifies hydrogen or lower-alkyl,R⁵ signifies amino or lower-alkyl, R⁷ signifies hydrogen or lower-alkyl,and R⁸ signifies hydrogen or halogen,

and pharmaceutically usable salts thereof.

The term "lower-alkyl" used here, alone or in combination, signifies astraight-chain or branched alkyl group with 1-6 C atoms such as methyl,ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert. butyl,n-pentyl and n-hexyl. The term "halogen" or "halo" embraces fluorine,chlorine, bromine and iodine.

Methyl and isopropyl are preferred lower-alkyl groups. Chlorine is apreferred halogen.

Examples of preferred compounds of formula I are:

4- 5-(4-Chlorophenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine,

4- 5-(3-methylphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine,

3-chloro-2- 4-(4-chlorophenyl)-5-pyridin-4-yl-imidazol-2-yl!phenylamine,

4- 5-(4-chlorophenyl)-2-(2,6-diisopropylphenyl)imidazol-4-yl!pyridine,

methyl 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzoate,

4- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!morpholine,

3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!dimethylamine,

1- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!-4-methylpiperazine,

4-5-(4-chlorophenyl)-2-(2,4,6-trimethyl-3-nitrophenyl)-imidazol-4-yl!pyridine,

3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylphenoland

4-5-(4-fluorophenyl)-2-(2-bromo-6-methylphenyl)-imidazol-4-yl!-pyridine.

The compounds of formula I which contain acidic functions can formpharmaceutically usable salts with bases such as alkali metal hydroxides(e.g. sodium hydroxide and potassium hydroxide), alkaline earth metalhydroxides (e.g. calcium hydroxide and magnesium hydroxide) and ammoniumhydroxide and the like. The compounds of formula I which contain basicfunctions can form pharmaceutically usable salts with acids. As suchsalts there come into consideration not only salts with inorganic acidssuch as hydrochloric acid or hydrobromic acid, sulphuric acid, nitricacid and phosphoric acid, but also salts with organic acids such asacetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid,malic acid, salicylic acid, citric acid, methanesulphonic acid,p-toluenesulphonic acid etc.

The present invention is accordingly concerned with compounds of formulaI and their pharmaceutically usable salts per se and for use astherapeutically active substances, a process for the manufacture ofthese compounds and their salts, medicaments which contain thesecompounds or salts and the production of these medicaments and the useof the compounds and their salts for the control of illnesses,especially hyperproliferative disorders such as atherosclerosis,psoriasis and tumours and for the treatment of alopecia, or for theproduction of a medicament for the treatment and prevention of suchdisorders.

The pharmacological activity of the compounds in accordance with theinvention can be determined on the basis of their activity as proteinkinase inhibitors and inhibitors of HaCaT-cell proliferation. Inparticular, the compounds in accordance with the invention are selectiveinhibitors of epidermal growth factor receptor (EGF-R) tyrosine kinase.

EGF-R plays a role in the development and metastation of certain humanmalignant diseases such as breast cancer, cancer of the liver and cancerof the prostate.

For all known functions and activities of EGF-R its tyrosine kinaseactivity is a determining factor. The inhibition of this enzymaticactivity by the compound of formula I can therefore be looked upon as ameasurement for the efficacy in the therapeutic treatment ofEGF-R-mediated hyperproliferative diseases such as certain forms ofcancer and psoriasis.

In contrast to the stimulating role of the EGF receptor in keratinocyteproliferation, in vitro and in vivo studies show that the activation ofthis receptor is a negative regulator of hair follicle activity. Thus,the injection of EGF inhibits hair growth in newborn mice (Moore et al.,J. Endocrinol 88, 293 1981!) and sheep (Chapman & Hardy from J. Biol.Sci. 41, 261 1988!) and the treatment of cultured human hair follicleswith EGF induces a catagen-like state (Philpott et al., J. Cell Sci. 97,463 1990!) with inhibition of hair fibre production. These findingssuggest that inhibition of EGF-R tyrosine kinase stimulates hair growthand lengthens the duration of the anagen phase of the hair cycle invivo.

The biological activity of the compounds in accordance with theinvention was tested in various test models which are describedhereinafter.

Tyrosine protein kinases

Inhibition of EGF-receptor Tyrosine Kinase

The activity of EGF-receptor tyrosine kinase is determined by measuringthe transfer of ³² P-labelled phosphate from ³² P-γ-ATP (10 μM) to thesubstrate RR-scr peptide* (0.75 mM). A membrane fraction from human A431cells is used as the enzyme. It is isolated according to Thom et al.,Biochem. J. 168, 187 (1977) and stored at -75° C. (4-6 mg protein/ml).The compounds are tested in 10% DMSO in a concentration of 0.001-100 μM.The incubation is carried out at 30° C. for a period of 30 minutes inTris buffer (25 mM, pH 7.4) which contains magnesium acetate (30 mM),sodium vanadate (0.5 mM), 0.5% BSA and 0.05% Triton X-100. The membranesare pre-incubated with 2 μM of EGF at 4° C. for 90 minutes. The test isstarted by adding the enzyme (2 μg of membrane protein) and terminatedby adding ice-cold KH₂ PO₄ (1M, pH 3.0). After centrifugation thelabelled peptide is separated from excess ATP in the supernatant byreversed phase HPLC. The peptide fraction is collected and theradioactivity is measured in a standard β-counter or on-line with aradiometer (Berthold). The inibitory activity of the test compound isexpressed as the mikromolar concentration which is required for 50%inhibition (IC₅₀ μM!).

*RR-src peptide= Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly!

Inhibition of p56^(Ick) tyrosine kinase

The activity of p56^(Ick) tyrosine kinase is determined by measuring thetransfer of ³² P-labelled phosphate from ³² P-γ-ATP (10 μM) to thesubstrate RR-src peptide (0.75 mM). Human recombinant p56^(Ick)(expressed in E. coli) is used as the enzyme.

It is purified from the soluble fraction by means of a monoclonalantibody column and stored at -75° C. The compounds are tested in 10%DMSO in a concentration of 0.001-100 μM, The incubation is carried outat 30° C. for a period of 30 minutes in HEPES buffer (50 mM, pH 6.9)which contains manganese chloride (11 mM) and 0.5% BSA. The test isstarted by adding the enzyme and terminated by adding ice-cold KH₂ PO₄(1M, pH 3.0). After centrifugation the radiolabelled peptide isseparated from excess ATP in the supernatant by reversed phase HPLC. Thepeptide fraction is collected and the radioactivity is determined in astandard β- counter or on-line with a radiometer (Berthold). Theinhibitory activity of the test compound is expressed as the micromolarconcentration which is required for 50% inhibition (IC₅₀ μM!).

Serine/threonine protein kinases

Inhibition of cAMP-dependent protein kinase (PKA)

The activity of PKA is measured by measuring the transfer of ³²P-labelled phosphate from ³² P-γ-ATP (10 μM) to the substrate histone H1(333 μg/ml) using partially purified PKA from hog brain (DEAEchromatography according to U. Kikkawa et al., Methods Enzymol. 99, 288,1983). PKA is activated by 2 μM of cAMP in Tris HCl buffer (20 mM, pH7.4). The compounds are tested in DMSO/buffer at a concentration of0.001-100 μM. The test is started by adding the enzyme, takes 2 minutesat 32° C. and is terminated by adding 20% trichloroacetic acid(containing 1% SDS and 1% sodium pyrophosphate). The precipitatedprotein, which contains the radiolabelled histone, is separated fromexcess ATP by filtration through a nitrocellulose membrane filter. Theradioactivity on the filter is determined in a scintillation counter.The inhibitory activity of the test compounds is expressed as themicromolar concentration which is required for 50% inhibition (IC₅₀μM!).

Inhibition of protein kinase C (PKC)

The activity of PKC is measured by measuring the transfer of ³²P-labelled phosphate from ³² P-γ-ATP (10 μM) to the substrate histone H1(200 μg/ml) using partially purified PKC from hog brain (DEAEchromatography according to U. Kikkawa et al., Methods Enzymol. 99, 288,1983). PKC is activated by phospholipid vesicle prepared by sonicating amixture of 0.05 ml of phosphatidylserine (10 mg/ml) and 0.005 ml ofdiolein (10 mg/ml) in 5 ml of Tris HCl buffer (20 mM, pH 7.4). Thecompounds are tested in DMSO/buffer at a concentration of 0.001-100 μM.The test is started by adding the enzyme, takes 2 minutes at 32° C. andis terminated by adding 20% trichloroacetic acid (containing 1% SDS and1% sodium pyrophosphate). The precipitated protein with the labelledhistone is separated from excess ATP by filtration over a nitrocellulosemembrane filter. The radioactivity on the filter is measured in ascintillation counter. The inhibitory activity of the test compound isexpressed as the micromolar concentration which is required for 50%inhibition (IC₅₀ μM!).

Inhibition of HaCaT cell proliferation

HaCaT is a spontaneous immortalized human keratinoycte cell line(Boukamp et al. 1988) which has been used many times as a model systemfor hyperproliferative keratinoyctes. The incorporation of ³H!-thymidine was used to quantify the growing cells in the S phase ofthe cell cycle. The cells were cultivated with a 3:1 mixture of DMEM/F12medium which had been supplemented with 5% FCS, EGF (10 μg/l),hydrocortisone (400 μg/l), cholera toxin (8.5 μg/l), insulin (5 μg/l),L-glutamine (2 mM) and penicillin/streptomycin. 200 μl of medium wereplaced in microtitre plates such that each sample contained 5000 cells.The test compounds were added in serial dilutions in the range of 1×10⁻⁸M to 1×10³¹ 5 M at the beginning of the cultivation. The cells wereincubated at 37° C. for 48 hours. For the last 6 hours ³ H!-thymidinewas added (1 mCi/sample). After digesting the cells with trypsin theamount of incorporated radioactivity was quantified with a liquidscintillation counter.

The inhibition of selected protein kinases in vitro and the inhibitionof cell proliferation in HaCaT-cells by these compounds are set forth inthe following Table.

    ______________________________________           IC.sub.50 (μM)           Isolated enzyme    Cells    Example  EGF-R     p56.sup.lck                              PCK    PKA  HaCaT    ______________________________________    1        0.34      2.2    >100   6.3  2    4        0.80      6.0    >100   190  2    16       0.31      2.2    n.t.   n.t. 0.8    7        0.13      3.1    100    0.47 3.5    9        0.14      3.8    80     6.0  0.23    11       0.26      5.1    >100   43   0.1    12       0.05      1.65   7.0    5.0  0.57    13       0.05      1.8    37     1.5  0.1    15       0.78      4.95   n.t.   n.t. 0.67    18       0.29      14     23     1.8  2    ______________________________________     n.t.: not tested

Stimulation of cell proliferation in cultured mouse hair follicles

Mouse hair follicles are isolated and cultured according to the methoddescribed by Buhl et al., J. Invest. Dermatol. 92, 315 (1989). Whiskerparts are removed from CD-1 mice aged 4 days and the hair follicles arecarefully separated from surrounding tissue under the microscope. Hairfollicles are cultured in M199 medium which contains 20% FBS and thecell proliferation is determined from the incorporation of ³H!-thymidine in DNA. The test compounds are dissolved in DMSO and addedin serial dilutions in the range of 1×10⁻⁸ to 1×10⁻⁶ M at the beginningof the cultivation. After 1 day 5 μCi/ml of ³ H!-thymidine are added tothe culture medium and the follicles are incubated for a further 3 days.The hair follicles are then washed with phosphate-buffered salinesolution in order to remove non-incorporated radioactivity and the DNAis solubilized by incubation with alkali overnight. The radioactivityincorporated into the follicular DNA is then measured using a liquidscintillation counter.

The incubation of mouse hair follicles with the compound of Example 1results in a stimulation of the cell proliferation with a maximum DNAsynthesis value of 211±17% (compared with controls) at a concentrationof 0.3 μM. The concentration which resulted in a half-maximumstimulation of the DNA synthesis (EC₅₀ value) was 0.1 μM. The activityof the compound of Example 1 in this culture system exceeded that ofknown hypotrichotic agents. For example, minoxidil stimulates hairfollicle DNA synthesis to 160±15% (compared with controls) and has aEC₅₀ value of 200 μM.

In accordance with the invention the compounds of formula I and theirpharmaceutically usable salts can be manufactured in accordance with theinvention by reacting a diketone of the general formula ##STR3##

wherein R⁷ and R⁸ have the above significance, with an aldehyde of thegeneral formula ##STR4##

wherein R¹, R², R³ and R⁵ have the significance given above and whereina hydroxy group in a compound of formula III can be present in protectedform,

in the presence of ammonia, cleaving off a hydroxy protecting groupwhich may be present and, if desired, functionally modifying reactivegroups present in a compound of formula I obtained and, if desired,converting a compound of formula I into a pharmaceutically usable salt.

The reaction of a diketone of formula II with an aldehyde of formula IIIand with ammonia can be carried out in a manner known per se. Forexample, a diketone of formula II can be reacted with an aldehyde offormula III and with ammonium acetate (a reagent which liberatesammonia) in an organic acid such as acetic acid at an elevatedtemperature, e.g. at about 50 to about 100° C.

A hydroxy group in a compound of formula III can be present in thereaction in accordance with the invention in protected form, for exampleas a benzyl ether, which can be removed from the reaction product in amanner known per se, in the case of the benzyl ether by e.g. catalytichydrogenation.

The diketones of formula II and aldehydes of formula III are known orcan be prepared in a manner known per se as described in the Examples orin analogy thereto.

Functional modification of reactive groups can comprise e.g. thesaponification of ester groups, the reduction of nitro groups to aminogroups and the alkylation of amino groups. These functionalmodifications can be carried out in a manner known per se, e.g. asdescribed in the Examples or in analogy thereto.

Acidic compounds of formula I can be converted into pharmaceuticallyusable salts by treatment with bases and basic compounds of formula Ican be converted into pharmaceutically usable salts by treatment withacids. Such reactions can be carried out in a manner known per se.

The compounds of formula I and their salts can be used as medicaments,e.g. in the form of pharmaceutical preparations.

The medicaments can be administered enterally, parenterally ortopically. Medicaments in the form of tablets, capsules, dragees,syrups, suspensions, solutions and suppositories are e.g. suitable forenteral administration. Medicaments in the form of infusion or injectionsolutions are suitable for parenteral administration.

The dosages in which the preparations are administered can varyaccording to the mode of use and route of use as well as according tothe requirements of the patient.

In the case of the oral administration of the compounds in accordancewith the invention there come into consideration in the case of adultsdosages of about 0.1-100 mg/kg, preferably 0.5-50 mg/kg, per day.

The preparations can be administered in one or more doses. Capsulescontaining about 5-500 mg of active ingredient comprise a preferredadministration form.

The preparations can contain inert or pharmacodynamically activeadditives. Tablets or granulates e.g. can contain a series of binders,fillers, carriers or diluents. Liquid preparations can be present, forexample, in the form of a sterile water-miscible solutions. Capsules cancontain a filler or thickener in addition to the active ingredient.Furthermore, flavour-improving additives as well as substances usuallyused as preservatives, stabilizers, moisturizers and emulsifiers as wellas salts for varying the osmotic pressure, buffers and other additivescan be present.

The previously mentioned carriers and diluents can comprise organic orinorganic substances, e.g. water, gelatine, lactose, starch, magnesiumstearate, talc, gum arabic, poly-alkylene glycols and the like. It is aprerequisite that all adjuvants used in the production of thepreparations are non-toxic.

For topical application the active ingredients are conveniently used inthe form of salves, tinctures, creams, solutions, lotions, sprays,suspensions, gels and the like. Salves and creams as well as solutionsare preferred. These preparations adapted for topical application can beproduced by mixing the process products as active ingredients withnon-toxic, inert solid or liquid carriers which are suitable for topicaltreatment and which are customary in such preparations.

For topical application there are conveniently suitable about 0.1-10%,preferably 0.3-2%, solutions as well as about 0.1-10%, preferably about0.3-2%, salves and creams.

If desired, an antioxidant, e.g. tocopherol, N-methyl-γ-tocopheramine aswell as t-butyl-hydroxyanisole or t-butyl-hydroxtolune, can be admixedwith the preparations.

The following Examples illustrate the invention in more detail.

EXAMPLE 1

A mixture of 12.3 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanedione and7.4 g of 2,4,6-trimethylbenzaldehyde in 125 ml of acetic acid containing40 g of ammonium acetate was stirred at 100° C. for 2 hours, then leftto cool to room temperature. The mixture was poured into a mixture of300 ml of ice-water and 200 ml of concentrated ammonia solution and themixture was extracted three times with ethyl acetate. After drying overanhydrous magnesium sulphate the solvent was evaporated. The residue waspurified by chromatography on silica gel with dichloromethane/methanol(9:1) and crystallized from ethyl acetate to yield 6.7 g of 4-5-(4-chlorophenyl)-2-(2,4,6-trimethyphenyl)imidazol-4-yl!pyridine, m.p.275° C.

EXAMPLES 2-17

The following compounds were prepared in analogy to Example 1:

2. 4-5-(4-fluorophenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine, m.p.252-254° C. (diethyl ether),

3. 4- 5-(4-chlorophenyl)-2-(2,6-dimethylphenyl)imidazol-4-yl!pyridine,m.p. 290-292° C. (ethyl acetate/hexane),

4. 4-5-(3-methylphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine, m.p.251-253° C. (diethyl ether),

5. 4-5-(4-chlorophenyl)-2-(2-chloro-6-methylphenyl)-imidazol-4-yl!pyridine,m.p. >260°C. (acetone),

6. 4-5-(4-chlorophenyl)-2-(2-bromo-6-methylphenyl)-imidazol-4-yl!pyridine,m.p. >260° C. (acetone/hexane),

7. 4-5-(4-chlorophenyl)-2-(2,6-diisopropylphenyl)imidazol-4-yl!pyridine,m.p. >260° C. (acetone/hexane),

8. 4-5-(4-fluorophenyl)-2-(2-bromo-6-methylphenyl)-imidazol-4-yl!pyridine,m.p. >260° C. (dichloromethane),

9. methyl 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!2,4,6-trimethylbenzoate,m.p. 228° C. (ethyl acetate/isopropyl ether),

10. 4-5-(4-chlorophenyl)-2-(2,6-dimethyl-3-nitrophenyl)-imidazol-4-yl!pyridine,m.p. 295-298° C. (ethyl acetate/hexane),

11. 4- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6,-trimethylbenzyl!morpholine,m.p. 239-240° C. (ethyl acetate),

12. 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6,-trimethylbenzyl!dimethylamine,m.p. 222° C. (acetonitrile),

13. 1- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6,-trimethylbenzyl!-4-methylpiperazine,m.p. 280° C. (ethyl acetate),

14. 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4-dimethylphenol,m.p. >300° C. (ethanol),

15. 4-5-(4-chlorophenyl)-2-(2,4,6-trimethyl-3-nitrophenyl)-imidazol-4-yl!pyridine,m.p. 295-299° C. (methanol/ethyl acetate),

16. 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6,-trimethylphenol,m.p. >300° C. (ethanol),

17. (2RS,6RS)- and (2R,6S)-4- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!-2,6-dimethylmorpholine,m.p. 163-170° C. (ethyl acetate).

EXAMPLE 18

A solution of 0.2 g of 4- 5-(4-chlorophenyl)-2-(2-chloro-6-nitrophenyl)imidazol-4-yl!pyridine in 20 ml of methanol was hydrogenated in thepresence of 0.1 g of 10% palladium/charcoal for 2 hours. The catalystwas filtered off and the solution was evaporated to dryness.Recrystallization from ethyl acetate yielded 0.1 g of 3-chloro-2-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!phenylamine, m.p.220-222° C.

The starting materials which are used in Examples 1-18, the preparationof which has not hitherto been described, can be prepared as describedhereinafter or in analogy thereto:

A. Ethanone derivatives (compounds of formula II)

1-(4-Chlorophenyl)-2-pyridin-4-yl-ethanedione

(i) 19.4 g of 4-pyridylmethyl isocyanide were added dropwise at -5° C.while stirring to a solution of 37.8 g of potassium tert-butylate in 400ml of tetrahydrofuran. The mixture was then treated with 23.1 g of4-chlorobenzaldehyde and stirred at -5° C. for a further 2 hours.Thereafter, 19.7 g of acetic acid were added dropwise at 0° C. whilestirring and the solid was filtered off. The residue was chromatographedon silica gel with dichloromethane/methanol (95:5) as the eluent andrecrystallized from dichloromethane/hexane. 25.0 g of (E/Z)-N-2-(4-chlorophenyl)-1-pyridin-4-yl-vinyl!formamide, m.p. 155-156° C.,were obtained.

(ii) A solution of 39.0 g of (E/Z)-N-2-(4-chlorophenyl)-1-pyridin-4-yl-vinyl!formamide in 430 ml of methanolwas treated at 0° C. with 112 ml of concentrated hydrochloric acid. Themixture was stirred at 32-34° C. for 16 hours. The mixture was thencooled to 0° C. and added dropwise while stirring at 0° C. to a solutionof 82.2 g of potassium hydroxide in 100 ml of water. The solid wasfiltered off and recrystallized from dichloromethane/hexane. 25.0 g of1-(4-chlorophenyl)-2-pyridin-4-yl-ethanone, m.p. 85-86° C., wereobtained.

(iii) A solution of 25 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanonein 285 ml of dioxan was treated with 20 g of selenium dioxide. Themixture was stirred at 100° C. for 1 hour and filtered. The solvent wasevaporated and the residue was dissolved in dichloromethane. Thesolution was washed three times with water, dried over anhydrousmagnesium sulphate and evaporated. The residue was dissolved in ethylacetate, the solution was filtered over silica gel and evaporated toyield 23.7 g of 1-(4-chlorophenyl)-2-pyridin-4-yl-ethanedione, m.p.119-120° C.

B. Benzaldehyde derivatives (compound of formula III)

2-Bromo-6-methylbenzaldehyde

(i) A solution of 9.52 g of (2-bromobenzylidene)phenylamine in 150 ml ofacetic acid was treated with 7.9 g of palladium(II) acetate. The mixturewas heated to reflux for 1 hour, then poured into 150 ml of water andextracted three times with dichloromethane. The combined organicextracts were washed with water, dried over anhydrous magnesium sulphateand evaporated to dryness. The residue was chromatographed on silica gelwith dichloromethane/methanol (99:1) as the eluent and yielded 10.3 g ofbis acetato(3-bromo-2-phenyliminomethyl-phenyl)palladium!(Pd-Pd), m.p.199-200° C.

(ii) A solution of 10.3 g of bisacetato(3-bromo-2-phenyliminomethylphenyl)palladium!(Pd-Pd) in 80 ml ofdichloromethane and 80 ml of acetone was treated with 90 ml of saturatedsodium chloride solution while stirring. After 10 minutes the solid wasfiltered off and yielded 6.1 g of bischloro(3-bromo-2-phenyliminomethylphenyl)palladium!(Pd-Pd), m.p.280-282° C.

(iii) A solution of 6.1 g of bischloro(3-bromo-2-phenylimino-methylphenyl)palladium!(Pd-Pd) in 225 ml ofabsolute benzene was treated with 7.9 g of triphenylphosphine underargon. Thereafter, the mixture was stirred at room temperature for afurther 30 minutes. 12.5 ml of a 1.6M solution of methyllithium indiethyl ether was added dropwise at 0 C. while stirring and the mixturewas thereafter stirred at room temperature for 1 hour. The mixture wasthen treated at 0° C. with 225 ml of 1N hydrochloric acid, filtered andthe solid was washed with diethyl ether. The combined organic extractswere washed twice with water, dried over anhydrous magnesium sulphateand evaporated to dryness. The residue was chromatographed on silica gelwith hexane/ethyl acetate (98:2) as the eluent and yielded 0.7 g of2-bromo-6-methylbenzaldehyde, m.p. 48-49° C.

2,6-Diisopropylbenzaldehyde

6.8 ml of a 1.6M solution of butyllithium in hexane was added dropwiseat -78° C. while stirring to a solution of 2.6 g of2-bromo-1,3-diisopropylbenzene in 16 ml of tetrahydrofuran. The mixturewas stirred at the same temperature for 30 minutes and thereaftertreated with a solution of 1.3 g of N-formylpiperdine in 1.5 ml oftetrahydrofuran. Thereafter, the mixture was left to warm to roomtemperature over a period of 6 hours. The mixture was cooled to 0° C.and treated with 12 ml of 3N hydrochloric acid. The aqueous solution wasextracted four times with diethyl ether and the combined organicextracts were washed with saturated sodium chloride solution, dried overanhydrous magnesium sulphate and evaporated to dryness. The residue waschromatographed on silica gel with dichloromethane as the eluent andyielded 1.07 g of 2,6-diisopropylbenzaldehyde as an oil.

2,6-Dimethyl-3-nitrobenzaldehyde

2 g of 2,6-dimethylbenzaldehyde were added at room temperature over aperiod of 15 minutes to a mixture of 20 ml of concentrated nitric acidand 10 ml of acetic acid. Thereafter, the mixture was stirred at roomtemperature for 5 minutes and poured on to ice-water. The mixture wasstirred for a further 5 minutes, filtered and the residue was dissolvedin dichloromethane. After drying over anhydrous magnesium sulphate thesolvent was evaporated. The residue was chromatographed on silica gelwith hexane/ethyl acetate as the eluent and yielded 1.23 g of2,6-dimethyl-3-nitrobenzaldehyde, m.p. 54-57° C. (from hexane), and 0.33g of 2,6-dimethyl-3,5-dinitrobenzaldehyde, m.p. 119-122° C. (fromtoluene/hexane).

2,4,6-Trimethyl-3-morpholin-4-yl-methylbenzaldehyde

A solution of 0.98 g of 3-chloromethyl-2,4,6-trimethylbenzaldehyde in 20ml of acetonitrile was treated with 0.87 ml of morpholine. The mixturewas stirred at room temperature for 4 hours and thereafter filtered. Thesolvent was evaporated and the residue was dissolved in ethyl acetate.The solution was washed twice with water, dried over anhydrous magnesiumsulphate and evaporated to dryness. Distillation of the residue yielded1.05 g of 2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldenhyde, b.p.150° C./0.3 Torr.

3-Dimethylaminomethyl-2,4,6-trimethylbenzaldehyde

3-Dimethylaminomethyl-2,4,6-trimethylbenzaldehyde, b.p. 150° C./0.3Torr, was prepared in analogy to the procedure described above for thepreparation of 2,4,6-trimethyl-3-morpholin-4yl-methylbenzaldehydemorpholin-4-yl-methylbenzaldehyde.

2,4,6-Trimethyl-3-(4-methylpiperazin-1-yl-methyl)-benzaldehyde

2,4,6-Trimethyl-3-(4-methylpiperazin-1-yl-methyl)-benzaldehyde, m.p. 90°C. (from acetonitrile), was prepared in analogy to the manner describedabove for the preparation of2,4,6-trimethyl-3-morpholin-4-yl-methylbenzaldehyde.

3-Hydroxy-2,6-dimethylbenzaldehyde

(i) A solution of 2.8 g of 2,6-dimethyl-3-nitrobenzaldehyde in 150 ml oftoluene was treated with 5 ml of ethylene glycol and 20 mg ofp-toluenesulphonic acid. The mixture was heated to reflux for 18 hours,with the water being separated using a separator. The mixture was leftto cool to room temperature and was washed twice with water. Afterdrying over anhydrous magnesium sulphate the solvent was evaporated andthe crystalline residue was crystallized from hexane. 3.0 g of2-(2,6-dimethyl-3-nitrophenyl)-1,3-dioxolane, m.p. 69-71° C., wereobtained.

(ii) A solution of 2.7 g of 2-(2,6-dimethyl-3-nitrophenyl)-1,3-dioxolanein 30 ml of ethyl acetate was hydrogenated in the presence of 0.2 g ofplatinum oxide for 45 minutes. The catalyst was filtered off and thesolution was concentrated to a crystalline residue. Recrystallizationfrom hexane yielded 2.35 g of2-(3-amino-2,6-dimethylphenyl)-1,3-dioxolane, m.p. 100-103° C.

(iii) A solution of 0.73 g of sodium nitrite in 2 ml of water was addedat 0° C. over a period of 15 minutes while stirring to a suspension of2.0 g of 2-(3-amino-2,6-dimethylphenyl)-1,3-dioxolane in 1.9 ml ofconcentrated sulphuric acid and 5.5 ml of water.

Thereafter, the mixture was stirred at room temperature for 15 minutesand then added while stirring over a period of 5 minutes at 110° C. to amixture of 1 ml of concentrated sulphuric acid and 15 ml of water. Themixture was heated to reflux while stirring for 1 hour, then left tocool to room temperature, filtered and washed with water to yield 1.55 gof 3-hydroxy-2,6-dimethylbenzaldehyde, m.p. 159-165° C. (from isopropylether).

3-Diethylaminomethyl-2,4,6-trimethylbehzaldehyde

3-Diethylaminomethyl-2,4,6-trimethylbenzaldehyde, b.p. 200° C./0.2 Torr,was prepared in analogy to the procedure described for the synthesis of2,4,6-trimethyl-3-morpholin-4-yl-methlbenzaldehyde.

(2RS,6RS)- and(2R,6S)-3-(2,6-dimethylmorpholin-4-yl-methyl)-2,4,6-trimethylbenzaldehyde

(2RS,6RS)- and(2R,6S)-3-(2,6-dimethylmorpholin-4-yl-methyl)-2,4,6-trimethylbenzaldehyde,m.p. 130° C. (hexane), was prepared in analogy to the proceduredescribed above for the synthesis of2,4,6-trimethyl-3-morpholin-4-yl-methyl-benzaldehyde.

Examples A-E illustrate the production of pharmaceutical preparations.

Example A

Hard gelatine capsules can be produced as follows:

    ______________________________________    Ingredient                mg/capsule    ______________________________________    1. Spray-dried powder containing 75% compound I                              20    2. Sodium dioctylsulphosuccinate                              0.2    3. Sodium carboxymethylcellulose                              4.8    4. Microcrystalline cellulose                              86.0    5. Talc                   8.0    6. Magnesium stearate     1.0    Total                     120    ______________________________________

The spray-dried powder, which is based on the active ingredient,gelatine and microcrystalline cellulose and which has an average activeingredient particle size of <1μ (measured using autocorrelationspectroscopy), is moistened with an aqueous solution of sodiumcarboxymethylcellulose and sodium dioctylsulphosuccinate and kneaded.The resulting mass is granulated, dried and sieved, and the granulateobtained is mixed with microcrystalline cellulose, talc and magnesiumstearate. The powder is filled into size 0 capsules.

Example B

Tablets can be produced as follows:

    ______________________________________    Ingredient            mg/tablet    ______________________________________    1. Compound I as a finely milled powder                          20    2. Powd. lactose      100    3. White corn starch  60    4. Povidone K30       8    5. White corn starch  112    6. Talc               16    7. Magnesium stearate 4    Total                 320    ______________________________________

The finely milled substance is mixed with lactose and a portion of thecorn starch. The mixture is moistened with an aqueous solution ofPovidone K30 and kneaded, and the resulting mass is granulated, driedand sieved. The granulate is mixed with the remaining corn starch, talcand magnesium stearate and pressed to tablets of suitable size.

Example C

Soft gelatine capsules can be produced as follows:

    ______________________________________    Ingredient     mg/capsule    ______________________________________    1. Compound I  5    2. Triglyceride                   450    Total          455    ______________________________________

10 g of compound I are dissolved in 90 g of medium-chain triglyceridewhile stirring and with inert gasification and protection from light.This solution is processed as a capsule fill mass to soft gelatinecapsules containing 5 mg of active ingredient.

Example D

A cream can be produced in a manner known per se from the constituentslisted hereinafter:

    ______________________________________                          Wt. %    ______________________________________    Compound of formula I   0.1-5    Cetyl alcohol           5.25-8.75    Arlacel 165 (glyceryl/PEG 100 stearate)                            3.75-6.25    Miglyol 818 (caprylic/capric/linoleic acid                            11.25-18.75    triglyceride)    Sorbitol solution       3.75-6.25    Na.sub.2 EDTA           0.075-0.125    Carbopol 934P (carbomer 934P)                            0.15-0.25    Butylated hydroxyanisole                            0.0375-0.0625    Methylparaben           0.135-0.225    Propylparaben           0.0375-0.0625    NaOH (10% solution)     0.15-0.25    Water q.s.              100.00    ______________________________________

Example E

A gel can be produced in a manner known per se from the constituentslisted hereinafter:

    ______________________________________                          Wt. %    ______________________________________    Compound of formula I    0.1-5    Pluronic L 101 (poloxamer 331)                             10.00    Aerosil 200 (silicon dioxide)                             8.00    PCL liquid (fatty acid ester)                             15.00    Cetiol V (decyl oleate)  20.00    Neobee oil (medium chain length triglyceride)                             15.00    Euhanol G (octyldodecanol), q.s.                             100.00    ______________________________________

The physical properties of the preparations can be altered by varyingthe ratio between the adjuvants in Examples D and E.

We claim:
 1. A compound of the formula ##STR5## wherein R¹ signifiesC₁₋₆ -alkyl or halogen, R² signifies hydrogen, hydroxy, nitro, C₁₋₆-alkoxycarbonyl, di(C₁₋₆ -alkyl)amino-C₁₋₆ -alkyl, morpholino-C₁₋₆-alkyl or 4-methylpiperazinyl-C₁₋₆ -alkyl, R³ signifies hydrogen or C₁₋₆-alkyl, R⁵ signifies amino or C₁₋₆ -alkyl, R⁷ signifies hydrogen or C₁₋₆-alkyl and R⁸ signifies hydrogen or halogen, or a pharmaceuticallyusable salt thereof.
 2. A compound as claimed in claim 1 which is 4-5-(4-chlorophenyl) -2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine. 3.A compound as claimed in claim 1 which is 4- 5-(3-methylphenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine.
 4. A compound asclaimed in claim 1 which is 3-chloro-2-4-(4-chlorophenyl)-5-pyridin-4-yl-imidazol-2-yl!phenyl-amine.
 5. Acompound as claimed in claim 1 which is 4-5-(4-chlorophenyl)-2-(2,6-diisopropylphenyl)imidazol-4-yl!pyridine.
 6. Acompound as claimed in claim 1 which is methyl 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzoate.7. A compound as claimed in claim 1 which is 4- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!morpholine.8. A compound as claimed in claim 1 which is 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethyl-benzyl!dimethylamine.9. A compound as claimed in claim 1 which is 1- 3-5-(4-chlorophenyl)-4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!-4-methylpiperazine.10. A compound as claimed in claim 1 which is 4-5-(4-(chlorophenyl)-2-(2,4,6-trimethyl-3-nitrophenyl)imidazol-4-yl!-pyridine.11. A compound as claimed in claim 1 which is 3-5-(4-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethyl-phenol.12. A compound as claimed in claim 1 which is 4-5-(4-fluorophenyl)-2-(2-bromo-6-methylphenyl)-imidazol-4-yl!-pyridine.13. A compound as claimed in claim 1 which is4-5-(4-fluorophenyl)-2-(2,4,6-trimethylphenyl)imidazol-4-yl!pyridine, 4-5-(4-chlorophenyl)-2-(2,6-dimethylphenyl)imidazol-4-yl!pyridine, 4-5-(4-chlorophenyl)-2-(2-chloro-6-methylphenyl)-imidazol-4-yl!pyridine,4- 5-(4-chlorophenyl)-2-(2-bromo-6-methylphenyl)-imidazol-4-yl!pyridine,4-5-(4-chlorophenyl)-2-(2,6-dimethyl-3-nitrophenyl)-imidazol-4-yl!pyridine3- 5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4-dimethylphenolor (2RS,6RS)- and (2R,6S)-4- 3-5-(4-chlorophenyl)-4-pyridin-4-yl-imidazol-2-yl!-2,4,6-trimethylbenzyl!-2,6-dimethylmorpholine.14. A pharmaceutical composition comprising an effective amount of acompound of the formula ##STR6## wherein R¹ signifies C₁₋₆ -alkyl orhalogen, R² signifies hydrogen, hydroxy, nitro, C₁₋₆ -alkoxycarbonyl,di(C₁₋₆ -alkyl)amino-C₁₋₆ -alkyl, morpholino-C₁₋₆ -alkyl or4-methylpiperazinyl-C₁₋₆ -alkyl, R³ signifies hydrogen or C₁₋₆ -alkyl,R⁵ signifies amino or C¹⁻⁶ -alkyl, R⁷ signifies hydrogen or C₁₋₆ -alkyland R⁸ signifies hydrogen or halogen, or a pharmaceutically usable saltthereof and a usual pharmaceutical carrier.
 15. A process for themanufacture of compounds set forth in claim 1, which process comprisesreacting a diketone of the general formula ##STR7## wherein R⁷ and R⁸have the significance given in claim 1, with an aldehyde of the generalformula ##STR8## wherein R¹, R², R³ and R⁵ have the significance givenin claim 1 and wherein a hydroxy group in a compound of formula III canbe present in protected form, in the presence of ammonia, and cleavingoff a hydroxy protecting group which may be present.
 16. A method forthe treatment of athersclerosis comprising administering to a host inneed of such treatment an effective amount of a compound of the formula##STR9## wherein R¹ signifies C₁₋₆ -alkyl or halogen, R² signifieshydrogen, hydroxy, nitro, C₁₋₆ -alkoxycarbonyl, di(C₁₋₆-alkyl)amino-C₁₋₆ -alkyl, morpholino-C₁₋₆ -alkyl or4-methylpiperazinyl-C₁₋₆ -alkyl, R³ signifies hydrogen or C₁₋₆ -alkyl,R⁵ signifies amino or C₁₋₆ -alkyl, R⁷ signifies or a pharmaceuticallyusable salt thereof.
 17. A method for the treatment of psoriasiscomprising administering to a host in need of such treatment aneffective amount of a compound of the formula ##STR10## wherein R¹signifies C₁₋₆ -alkyl or halogen, R² signifies hydrogen, hydroxy, nitro,C₁₋₆ -alkoxycarbonyl, di(C₁₋₆ -alkyl)amino-C₁₋₆ -alkyl, morpholino-C₁₋₆-alkyl or 4-methylpiperazinyl-C₁₋₆ -alkyl, R³ signifies hydrogen or C₁₋₆-alkyl, R⁵ signifies amino or C₁₋₆ -alkyl, R⁷ signifies hydrogen or C₁₋₆-alkyl and R⁸ signifies hydrogen or halogen, or a pharmaceuticallyusable salt thereof.
 18. A method for the treatment or prophylaxis oftumors comprising administering to a host in need of such treatment aneffective amount of a compound of the formula ##STR11## wherein R¹signifies C₁₋₆ -alkyl or halogen, R² signifies hydrogen, hydroxy, nitro,C₁₋₆ -alkoxycarbonyl, di(C₁₋₆ -alkyl)amino-C₁₋₆ -alkyl, morpholino-C₁₋₆-alkyl or 4-methylpiperazinyl-C₁₋₆ -alkyl, R³ signifies hydrogen or C₁₋₆-alkyl, R⁵ signifies amino or C₁₋₆ -alkyl, R⁷ signifies hydrogen or C₁₋₆-alkyl and R⁸ signifies hydrogen or halogen, or a pharmaceuticallyusable salt thereof.
 19. A method for the treatment of alopeciacomprising administering to a host in need of such prophylaxis ortreatment an effective amount of a compound of the formula ##STR12##wherein R¹ signifies C₁₋₆ -alkyl or halogen, R² signifies hydrogen,hydroxy, nitro, C₁₋₆ -alkoxycarbonyl, di(C₁₋₆ -alkyl)amino-C₁₋₆ -alkyl,morpholino-C₁₋₆ -alkyl or 4-methylpiperazinyl-C₁₋₆ -alkyl, R³ signifieshydrogen or C₁₋₆ -alkyl, R⁵ signifies amino or C₁₋₆ -alkyl, R⁷ signifieshydrogen or C₁₋₆ -alkyl and R⁸ signifies hydrogen or halogen, or apharmaceutically usable salt thereof.